Malaria is a major cause of morbidity and mortality in the world today. Despite intensive efforts to control this disease, approximately 200 million people are newly infected with malaria each year. The current proposal has been designed for the discovery and characterization of agents that show promise for the treatment of malaria. Natural products have already demonstrated their potential as antimalarials in the plant compounds, quinine and artemisinin, and it is suggested that continued progress in natural drug discovery can be realized through a multidisciplinary research program such as that existing at the University of Illinois at Chicago. Based on preliminary studies, plant extracts have already been identified as promising leads for the isolation of potential antimalarial agents. As described herein, these plants will be collected, extracted and subjected to in vitro bioassay protocols utilizing cultured Plasmodium falciparum strains and cultured mammalian cells. Plant extracts demonstrating a significant capacity to inhibit the growth of P. falciparum in vitro will be subjected to bioassay-directed fractionation procedures. Upon further antimalarial and cytotoxicity testing, the active principles from fractions which exhibit elective antimalarial activity will then be isolated and their structures elucidated. During the course of these studies, additional plant leads will be selected by perusal of the literature and utilization of the NAPRALERT database, and active leads will be subjected to the procedures described above. A second major area of research will focus on defining antimalarial mechanisms of action. Promising active compounds currently available and those isolated during the current studies will be introduced into a secondary regimen of assays intended to define mechanisms of antiplasmodial action. The secondary assays will examine (i) the ability of isolates to enhance or modulate the activity of existing antimalarial agents, (ii) the effects of the isolates on (ii) parasite-mediated host-erythrocyte permeability, (iii) intracellular oxidative stress, and (iv) the activity of P. falciparum haem polymerase. Based on these data and the structures of the active principles, in collaboration with Walter Reed Army Institute of Research, more advanced testing will be performed with in vivo test systems. The ultimate goal of this proposal is to discover and characterize novel agents from natural products for the treatment of human malaria.